LPS-induced coagulation and inflammation are important components of the pathogenesis of bacterial sepsis. In the United States, sepsis is the leading cause of death in non-coronary intensive care units. The objective of this proposal is to determine the role of the PI3K-Akt signaling pathway in suppressing LPS- induced coagulation and inflammation. The overall hypothesis is that the PI3K-Akt pathway negatively regulates LPS-induced coagulation and inflammation. Specific Aim 1 will characterize the role of PI3K-Akt pathway activation in LPS-induced cytokine and tissue factor production by macrophages. We will employ a genetic approach that either increases (PTEN-/-) or decreases (p85alpha-/-) PI3K-Akt pathway activation. Specific Aim 2 will evaluate whether the inhibitory effect of simvastatin on LPS-induced coagulation and inflammation involves activation of PI3K-Akt signaling. We hypothesize that wortmannin, a PI3K inhibitor, will block the anti-inflammatory and anticoagulant effects of simvastatin in LPS-treated macrophages and in a mouse endotoxemia model. Ultimately, characterization of the involvement of this pathway in LPS-induced inflammation may allow for development of novel strategies that can be used to treat sepsis. [unreadable] [unreadable] [unreadable]